Coagulation consists of a humoral and a cellular response. The former leads to the conversion of soluble fibrinogen into insoluble fibrin, the latter consists of activation of platelets leading to a platelet plug. Platelet plugs, fibrin threads and included red blood cells together constitute a blood clot. A key molecule in clot formation is thrombin. This protease converts soluble fibrinogen into the insoluble fibrin, it activates platelets, and converts a number of other factors including factors XI, VIII and V, into active species.
Pathological thrombosis refers to clot formation that is not part of a normal hemostatic process and that may result in disease symptoms. For example, thrombosis on an atherosclerotic plaque in a coronary artery may result in acute myocardial infarction and can be considered as a type of pathological thrombosis. Deep venous thrombosis and thrombosis on vascular grafts are other examples of pathological thrombosis.
Current anticoagulant drugs inhibit the basal pathway of coagulation: heparin (via antithrombin III) hits thrombin, factors Xa and IXa, coumarins inhibit the synthesis of prothrombin, factors VII, IX and X, whereas LMW heparin mainly inhibits factor Xa. The therapeutic window of these drugs is narrow, requiring careful monitoring of patients. Some of the newer anticoagulant drugs under development target at the FVIII/FIX amplification loop.
Considering the severe bleeding tendency resulting from a complete deficiency of factor VIII or IX, in hemophilia A or B, respectively, targeting at this level likely will also require careful monitoring to prevent the risk of bleeding side effects, particularly at overdosing.
Factor XI is not a target for current anticoagulants. This is mainly due to the fact that factor XI deficiency, in contrast to a deficiency of factor VIII or IX, does not result in a severe bleeding tendency. As a matter of fact many factor XI deficient persons never experience a severe bleeding episode. Only two studies have been performed with antibodies, in both cases polyclonal, against factor XI that inhibit the function of factor XI in vivo, either by inhibiting the activity of the molecule or by preventing its activation. In a first study (Minnema et al., 1998, J Clin Invest. 101:10-14) polyclonal antibodies against rabbit factor XI were used to evaluate the effect of factor XI blockade on clot formation in vivo in an experimental thrombosis model in rabbits. Incorporation of anti-factor XI antibodies in jugular vein thrombi resulted in an almost twofold increase in endogenous thrombolysis compared with a control antibody. A similar effect was observed when the anti-factor XI antibody was administered systemically.
The effect of administration of neutralizing polyclonal goat anti-factor XI-antibodies on the accumulation of platelets and fibrin on arterio-venous grafts in baboons was topic of another study to evaluate factor XI as target for antithrombotic therapy (Gruber and Hanson, 2003, Blood 102:953-955). In that study the role of factor XI-dependent thrombus propagation under arterial flow conditions was investigated. Under the conditions used rapid thrombus growth was produced on the grafts of Dacron or Teflon deployed into arteriovenous shunts in baboons treated with anti-human factor XI antibody. Administration of the polyclonal antibodies against factor XI markedly reduced intraluminal thrombus growth on both surfaces. The antithrombotic effect of the polyclonal antibodies against factor XI was found to be comparable with that of heparin at doses that significantly prolonged the partial thromboplastin time, prothrombin time, and bleeding time, whereas anti-FXI antibodies only affected the partial thromboplastin time but not prothrombin time and bleeding time.
There is however still a need in the art for anti-coagulant therapies based on antigen binding molecules that target factor XI.